Skip to main content
Log in

The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia

A double-blind, placebo-controlled, prospective study

  • Originals
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Summary

We have studied the effects of 12 weeks of lovastatin (20 mg per day) on platelet function and thromboxane formation in 18 patients with type II hypercholesterolaemia in a double-blind, placebo-controlled, prospective study.

Lovastatin significantly reduced total serum and LDL-cholesterol by 20% and 25% respectively. Washed platelets of lovastatin-treated patients had significantly reduced collagen-induced aggregation and thromboxane formation ex vivo. There was no change in ADP-induced platelet aggregation, but a significant increase in prostacyclin (iloprost)-stimulated platelet cyclic AMP concentrations in lovastatin-treated patients. This was associated with a significant increase in the number of prostacyclin receptors in platelet membranes prepared from lovastatin-treated patients. There was also an increase in platelet thromboxane receptors. There were no such changes in the placebo group.

These data confirm our original observation of normalization of platelet function in hypercholesterolaemia by HMGCoA reductase inhibitors and suggest changes in platelet membrane composition at the megakaryocyte level as a possible site of action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aviram M (1989) Modified forms of low density lipoprotein affect aggregation in vitro. Thromb Res 53: 561–567

    Google Scholar 

  2. Barrow SE, Stratton PD, Benjamin N, Brassfield T, Ritter JM (1991) Reduction of LDL cholesterol by pravastatin does not influence platelet activation in patients with mild hypercholesterolemia at risk of coronary heart disease. Br J Clin Pharmacol 32: 127–129

    Google Scholar 

  3. Bruckdorfer KR, Buckley S, Hassall DG (1984) The effect of LDL on the synthesis of cyclic nucleotides induced by prostacyclin in isolated platelets. Biochem J 223: 189–196

    Google Scholar 

  4. Carvalho ACA, Colman RW, Lees RS (1974) Platelet function in hyperlipoproteinemia. New Engl J Med 290: 434–438

    Google Scholar 

  5. Colli S, Lombroso M, Maderna P, Tremoli E, Nicosia S (1983) Effects of PGI2 on platelet aggregation and adenylate cyclase activity in human type IIa hypercholesterolemia. Biochem Pharmacol 32: 1989–1993

    Google Scholar 

  6. Colli S, Maderna P, Tremoli E, Baraldi A, Rovati GE, Gianfranceschi G, Nicosia S (1985) Prostacyclin-lipoprotein interactions. Studies on human platelet aggregation and adenylate cyclase. Biochem Pharmacol 34: 2451–2457

    Google Scholar 

  7. Colli DW, Maderna P, Accomazzo MR, Nicosia S, Tremoli E (1989) Iloprost binding and inhibition of aggregation in platelet rich plasma. Differences between normal and type IIa hypercholesterolemic subjects. Biochem Pharmacol 38: 39–45

    Google Scholar 

  8. Davi G, Maderna M, Novo S, Barbagallo CM, Mogavero A, Notarbartolo A, Strano A (1989) Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients. Atherosclerosis 79: 79–83

    Google Scholar 

  9. Di Minno G, Cerbone AM, Cirillo F, Postiglione A, Colucci M, Semeraro N, Scarpato N, Gnasso A, Margaglione M, Galotta G (1990) Hemostatic variables in homozygous familial hypercholesterolemia. Effect of regular plasma cholesterol removal by low density lipoprotein apheresis. Arteriosclerosis 10: 1119–1126

    Google Scholar 

  10. Eynard AR, Tremoli E, Caruso D, Magni F, Sirtori CR, Galli C (1986) Platelet formation of 12-hydroxyeicosatetraenoic acid and thromboxane B2 is increased in type IIa hypercholesterolemic subjects. Atherosclerosis 60: 61–66

    Google Scholar 

  11. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 18: 499–502

    Google Scholar 

  12. Gotto AM (Chairman) (1989) American Heart Association Conference report on cholesterol. Circulation 80: 717–748

    Google Scholar 

  13. Jakubowski JA, Ardlie NG, Nestel PJ (1980) The effect of hypercholesterolaemia on the lipid composition and ability of human platelets to accumulate cyclic AMP. Prostaglandins Med 5: 457–467

    Google Scholar 

  14. Jaschonek K, Funk M, Muller CP (1989) Modulation of platelet [3H] iloprost binding by cholesterol, dibucaine and pentoxifylline. In: Schrör K, Sinzinger H (eds) Prostaglandins in Clinical Research. Liss, New York, pp 321–325

    Google Scholar 

  15. Kramer RM, Jakubowski JA, Vaillancourt R, Deykin D (1982) Effect of membrane cholesterol on phospholipid metabolism in thrombin-stimulated platelets. J Biol Chem 257: 6844–6849

    Google Scholar 

  16. L'Abbate R, Modesti PA, Fortini A, Lombardi A, Matucci M, Gensini GF, Neri Serneri GG, Fellin R, Valerio G, Crepaldi G (1985) Decreased number of PGD2 binding sites on platelets from patients with type IIa hyperlipoproteinemia. Atherosclerosis 54: 167–175

    Google Scholar 

  17. Löbel P, Steinhagen-Thiessen E, Schrör K (1988) Cholestyramine treatment of type IIa hypercholesterolemia normalizes platelet reactivity against prostacyclin. Eur J Clin Invest 18: 256–260

    Google Scholar 

  18. Malle E, Sattler W, Prenner E, Leis HJ, Karàdi I, Knipping G, Romics L, Kostner GM (1991) Platelet membrane fluidity in type IIA, type IIB, and type IV hyperlipoproteinemia. Atherosclerosis 87: 159–167

    Google Scholar 

  19. Martin JF, Slater DN, Kishk YT, Trowbridge EA (1985) Platelet and megakaryocyte changes in cholesterol induced experimental atherosclerosis. Arteriosclerosis 5: 604–612

    Google Scholar 

  20. Mosconi C, Colli S, Tremoli E, Galli C (1988) Phosphatidylinositole (PI) and PI-associated arachidonate are elevated in platelet total membranes from type IIa hypercholesterolemic subjects. Atherosclerosis 72: 129–134

    Google Scholar 

  21. Neaton JD, Wentworth D (1992) Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Arch Int Med 152: 56–64

    Google Scholar 

  22. Ogletree ML, Harris DN, Greenberg R, Haslanger MF, Nakane M (1985) Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist. J Pharmacol Exp Ther 234: 435–441

    Google Scholar 

  23. Oliva DW, Maderna P, Accomazzo MR, Nicosia S, Tremoli E (1989) Iloprost binding and inhibition of aggregation in platelet rich plasma. Differences between normal and type IIa hypercholesterolemic subjects. Biochem Pharmacol 38: 39–45

    Google Scholar 

  24. Prisco D, Rogasi PG, Paniccia R, Coppo M, Abbate R, Gensini GF (1988) Altered lipid composition and thromboxane A2 formation in platelets from patients affected by IIa hyperlipoproteinemia. Thromb Res 50: 593–604

    Google Scholar 

  25. Schröder H, Strobach H, Schrör K (1992) Nitric oxide but not prostacyclin is an autocrine endothelial mediator. Biochem Pharmacol 43: 533–537

    Google Scholar 

  26. Schrör K (1990) Platelet reactivity and arachidonic acid metabolism in type II hyperlipoproteinemia and its modification by cholesterol lowering agents. Eicosanoids 3: 67–73

    Google Scholar 

  27. Schrör K and Seidel H (1988) Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay. NS Arch Pharmacol 337: 177–186

    Google Scholar 

  28. Schrör K, Löbel P, Steinhagen-Thiessen E (1989) Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia. Eicosanoids 2: 39–46

    Google Scholar 

  29. Shattil SJ, Anaya-Galiudo R, Bennett J, Colman RW, Cooper RA (1975) Platelet hypersensitivity induced by cholesterol incorporation. J Clin Invest 55: 636–643

    Google Scholar 

  30. Smith CM, Burris SM, Hunnighake DB, White JG (1988) Altered platelet deformability in patients with type IIa and type IV hyperlipoproteinemia. Am J Hematol 27: 247–252

    Google Scholar 

  31. Sorisky A, Kucera GL, Rittenhouse SE (1990) Stimulated cholesterol-enriched platelets display increased cytosolic Ca2+ and phospholipase A activity independent of changes in inositol triphosphates and agonist/receptor binding. Biochem J 265: 747–754

    Google Scholar 

  32. Strano A, Davi G, Averna M, Rini GB, Novo S, DiFede G, Mattina A, Notarbartolo A (1982) Platelet sensitivity to prostacyclin and thromboxane production in hyperlipidemic patients. Thromb Haemostasis 48: 18–20

    Google Scholar 

  33. Stuart MJ, Gerrard JM, White JG (1980) Effect of cholesterol on production of thromboxane B2 by platelets in vitro. New Engl J Med 302: 6–10

    Google Scholar 

  34. Tremoli E, Folco G, Agradi E, Galli C (1979) Platelet thromboxane and serum cholesterol. Lancet 1: 106–107

    Google Scholar 

  35. Tremoli E, Maderna P, Colli S, Morazzoni G, Sirtori M, Sirtori CR (1984) Increased platelet sensitivity and thromboxane B2 formation in type IIa hyperlipoproteinaemic patients. Eur J Clin Invest 14: 329–333

    Google Scholar 

  36. Warner P, Patscheke H (1980) Hyperreactivity by an enhancement of the arachidonate pathway of platelets treated with cholesterol-rich phospholipid dispersions. Thromb Res 18: 439–451

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaczmarek, D., Hohlfeld, T., Wambach, G. et al. The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia. Eur J Clin Pharmacol 45, 451–457 (1993). https://doi.org/10.1007/BF00315517

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00315517

Key words

Navigation